Integrated adipose tissue transcriptomic and miRNA remodeling identifies molecular pathways associated with residual cardiovascular risk after weight loss

Abstract Background Weight loss improves cardiometabolic health, yet substantial inter-individual variability remains in residual cardiovascular risk. Here, we investigated whether post-weight loss adipose tissue (AT) molecular remodeling is associated with this variability. Methods Sixty-six individuals with obesity underwent an 8-week low-calorie diet followed by a 6-month dietary intervention. Clinical variables, 3′-end mRNA sequencing and small non-coding RNA profiling of subcutaneous AT were simultaneously analyzed using sparse Partial Least Square (sPLS) related methods to identify candidate molecular signatures associated with SCORE2, an estimate of 10-year cardiovascular risk. Results Weight loss significantly improved body composition, insulin sensitivity, inflammation and SCORE2. However, SCORE2 trajectories differed during follow-up, with a greater rebound in men than women. Multi-omics integration identified AT molecular remodeling associated with cardiovascular risk at the end of the intervention. Higher SCORE2 was associated with AT expression patterns involving immune responses, apoptosis, mTOR signaling, mitochondrial respiratory chain activity and glucose metabolism, including glycolysis, insulin signaling and pyruvate oxidation. Most contributing microRNAs (miRs) exhibited reduced expression, consistent with de-repression of target genes regulating cell turnover, immunity and carbohydrate metabolism. Integration of mRNA and small non-coding RNA signatures revealed significant convergence on glucose metabolism, insulin signaling and mTOR pathways, while the sPLS-derived association network highlighted miR-125a-5p as a highly interconnected miRNA. Conclusions AT transcriptional remodeling during the post-weight loss period is strongly associated with residual cardiovascular risk after weight loss. Coordinated changes in immune, metabolic pathways and miRs may provide molecular signatures of inter-individual differences in cardiovascular risk and identify candidate pathways for further investigation. Trial registration DiOGenes clinical trial (NCT00390637). Clinical trial identifier NCT00390637. GEO deposits GSE141221.